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- Title
Selective Inhibition of Lysine‐Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple‐Negative Breast Cancer Therapy.
- Authors
Yang, Guan‐Jun; Wang, Wanhe; Mok, Simon Wing Fai; Wu, Chun; Law, Betty Yuen Kwan; Miao, Xiang‐Min; Wu, Ke‐Jia; Zhong, Hai‐Jing; Wong, Chun‐Yuen; Wong, Vincent Kam Wai; Ma, Dik‐Lung; Leung, Chung‐Hang
- Abstract
Abstract: Lysine‐specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A‐tri‐/di‐methylated histone 3 protein–protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple‐negative breast cancer (TNBC) cell lines, MDA‐MB‐231 and 4T1. Finally, 1 exhibited potent anti‐tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal‐based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.
- Subjects
BREAST cancer treatment; LYSINE specific demethylase 1; ENZYME inhibitors; RHODIUM compounds; METAL complexes; LIGANDS (Chemistry)
- Publication
Angewandte Chemie, 2018, Vol 130, Issue 40, p13275
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201807305